Stroke is the leading cause of disability and the fourth leading cause of death amongst adults in the United States. Plasminogen activator remains the only food and drug administration (FDA)-approved drug for stroke treatment. However this treatment has significant limitations in efficacy, safety, and the window of effectiveness. The lack of any effective restorative pharmacological approaches indicates the urgent need of stem cell-based therapies. A new class of autologous neural stem cells (NSCs) known as induced pluripotent stem cell derived NSCs (iNSCs) with abilities to differentiate into neurons, astrocytes and oligodendrocytes and to integrate into damaged brain tissue represents an exciting regenerative therapeutic population. However, these cells show significant variability in efficacy due to their survival issues under the cytotoxic environment after stroke with high levels of reactive oxygen species (ROS) and inflammatory cytokines. This suggests that pre-treatment of the damaged brain with anti-oxidant and anti-inflammatory agents appropriately delivered to the target tissue would significantly improve survival of transplants and ultimately tissue and functional outcomes. We recently developed a highly lipophilic biodegradable nanoparticle (NP) delivery platform with ability to cross the blood brain barrier (BBB) and deliver anti-oxidant insie the mitochondrial matrix rich in ROS and anti-inflammatory agent in the white matter of the brain where inflammation is diffused. With this success, we hypothesized that development of therapeutic options based on combined NP delivered neuroprotectant-stem cell therapy after stroke in a large animal model such as pig with brains similar to human can be extremely beneficial. To construct this NP platform and to demonstrate its potential, we have defined the following Specific Aims: (1) Construction and in vitro optimization of a BBB penetrating targeted biodegradable NP containing mitochondria acting anti-oxidant and anti-inflammatory agents; (2) Safety, toxicity, distribution in normal piglet and therapeutic efficacy in a pig middle cerebral artery occlusion (MCAO) ischemic injury model; (3) Combined therapeutic NP-stem cell therapy in a pig MCAO stroke model. This study will provide a potential nanomedicine platform for combined neuroprotectant-stem cell therapy after stroke. The targeted NPs are simple in composition and constructed from a well characterized biodegradable targeting moiety appended polymer which will be extremely beneficial for clinical translation.